APPLICANT'S ABSTRACT: This project seeks to identify regions of the human genome that contain genetic loci that influence the susceptibility to cigarette smoking (CS) and nicotine dependence (ND). In 1967, the US Surgeon General's report concluded that "smoking is the prototypical substance-abuse dependency." The US contains 45 million nicotine- dependent smokers and tobacco use is responsible for over 400,000 deaths annually. Twin and adoption studies in man have conclusively shown that genetic factors substantially influence the risk for CS and ND, and these results are confirmed by studies in rodents. Specifically, we propose to study three epidemiologic samples for which we are already funded to collect DNA and information on lifetime smoking habits. We request support to select from these samples 400 dizygotic twin or non-twin sibling pairs particularly infomative for CS/ND. We will select pairs in which either both members are high nicotine- dependent regular smokers or one member is so classified and his sibling experimented with cigarettes but never developed a regular smoking habit. On the first 200 of these pairs, we will complete a genome wide scan using 400 highly polymorphic markers. Positive findings will then be replicated in the next 200 pairs. We will also study additional sibling pairs to clarify the genetic basis of low nicotine-dependent regular smoking. A variety of statistical methods, including multipoint mapping and multivariate genetic analyses, will be used to detect and localize individual susceptibility genes for CS/ND in the selected samples. Further analyses will permit us to clarify the spectrum of action of these loci, determining whether they also impact on personality and/or the risk for psychiatric illness or other forms of drug abuse/dependence. Once chromosomal regions containing susceptibility genes for CS/ND have been identified, the tools of molecular biology can, in subsequent work, be applied to identify the specific genes and understand their mode of action. This will provide major insights into the brain mechanisms involved in susceptibility to CS and ND.